1. Field of the Invention
The present invention relates to a device and method for performing blood coagulation assays, particularly prothrombin times; activated partial thromboplastin times and other clotting tests. It also relates to a portable device that is easy is to use, accurate and rapid for routine testing at a patient's bedside, physician's office, operating room, or even at a patient's home for patients under anticoagulant therapy. The invention comprises a disposable test strip, and a piezoelectric sensor for detecting signals collected as the sample proceeds to clot formation.
Blood clotting is a result of a series of biochemical reactions where fibrinogen turns into cross- linked polymeric fibrin through several enzymatic reactions (known as the extrinsic and intrinsic coagulation pathways). Determination of coagulation parameters, such as prothrombin time (PT) and activated partial thromboplastin time (APTT) and other coagulation parameters has a large impact on the cure and prevention of thrombolic and/or fibrinolytic abnormalities.
Point-of-care testing uses advances in technology to improve turn-around-time. New point-of-care technologies based on miniaturized whole blood biosensors allow results to be obtained at the hospital bedside in minutes with accuracy and precision equivalent to that provided by the central clinical laboratory. The advent of these technologies, and the demands of physicians for more timely diagnostic test results in order to facilitate the patient management process, has resulted in rapid growth of this specific clinical testing segment.
Point-of-care testing provides health care quickly, effectively, and efficiently to the patient at the time and in the manner that it does the most good. It extends across the entire health care spectrum, from early diagnosis and timely institution of therapeutic measures during a visit in a doctor's office to optimizing critical care in a tertiary hospital setting and close monitoring and rapid intervention in an intensive care unit (ICU). It also provides cost-effective health care by maximizing the efficacy and efficiency of the providers.
Data from extensive experience with self-testing demonstrates that increasing the frequency of prothrombin time (PT) testing in turn increases a patient's time within therapeutic range. In order to reduce thromboembolic complications at both ends of the coagulation spectrum, tight control of a patient's PT (INR) is essential. It has been estimated that 40,000 strokes could be avoided each year if warfarin were prescribed for arterial fibrillation patients. Warfarin is used in long-term anticoagulation therapy. Almost 2 million Americans take either heparin or warfarin for as long as they live after having a cardiovascular incident or disease. Most warfarin users have experienced aterial fibrillation, are at risk for deep vein thrombosis, or have recently had a stroke or transmural myocardial infarction.
Clinical studies have indicated that self-testing may improve patient treatment over the current method of monitoring anticoagulation therapy. Studies have shown that patients who self-monitor their anticoagulant drug usage are within the correct therapeutic range 80%-90% of the time, versus 60%-70% when monitored by an anticoagulant management service or a physician. Point-of-care instrumentation also provides speedy, on-site analysis that can be used in hospital operating rooms to monitor the effectiveness of drugs administered to prevent or dissolve blood clots.
Lack of accuracy and precision, difficulty of doing quality control and higher cost per test has resulted in a less rapid development than had been predicted for point-of-care products. An accurate, yet precise and reliable point-of-care device is needed for ease of use, efficiency, simplicity and compatibility with automated laboratory instrumentation.
2. Related Art
U.S. Pat. Nos. 5,110,727 and 4,849,340, to Oberhardt relates to a commercial point-of-care system TAS (Thrombolytic Assessment System). The TAS system uses paramagnetic iron oxide particles (PIOP)/dry chemistry technology. It is based on near-infrared sensing of the motion of PIOP contained in a dry reagent, situated as a film on the surface of a flat-capillary reaction chamber mounted on a plastic test card. The PIOP are subjected to an oscillating magnetic field generated by the instrument in which the test card is placed. When blood or plasma is added to a sample well of the test card, the sample enters the reaction chamber, reconstituting the reagent and freeing the PIOP so that they can move in response to changes in the magnetic field with time. The PIOP motion changes when an in vitro thrombus forms. This change results from PIOP entrapment during fibrin polymerization or release during fibrinolysis, providing a kinetic response curve, from which the analyzer determines clotting time and a parameter characterizing fibrinolysis process.
U.S. Pat. No. 3,695,842, to Minz, assigned to International Technydyne Corporation has a precision magnet in a reagent-containing test tube. When the test tube is filled with sample and inserted in a test well containing a magnetic detector, the tube slowly rotates. When the clot begins to form a change in the position of the magnet is detected.
A second patent assigned to International Technydyne Corporation (U.S. Pat. No. 5,372,946) discloses a disposable cuvette within which is formed a capillary conduit having at least one restricted region. The blood is forced to flow through the restricted region back and forth within a test channel. Two photo-optical detectors are used to measure the speed of sample movement.
U.S. Pat. No. 4,756,884 discloses a technology developed by Biotrack based on optical measurement of a speckle pattern from cells or particles from a sample illuminated by coherent light and flowing in a long capillary track of a plastic reagent-containing cartridge. When clotting occurs, the speckle pattern measurement indicates cessation of flow in the capillary track.
U.S. Pat. No. 4,599,219 assigned to Hemotec discloses a cylindrical plastic cartridge with a plunger assembly terminating in a "flag" at one end and a "daisy" at the other end. The plunger, situated in a reaction chamber above a reagent chamber, is moved by an external mechanical actuator. Flag movement through the clot reaction chamber is timed by a photo-optical detector, the end point being established when fibrin forms on the daisy and slows the plunger movement.
U.S. Pat. No. 5,167,145 describes a technology using infrared electromagnetic energy. Infrared electromagnetic transmission changes through a sample from a source of infrared energy to suitable detection electronics producing a peak signal representing the clotting time.
U.S. Pat. No. 5,601,995 to Exner and assigned to Gradipore Limited, Australia discloses a method where a blood sample is applied to a porous sheet and at least one of a spreading extent and a spreading rate are measured by either an optical property, or an electrical potential across the porous sheet to determine the propensity of the sample to coagulate.
U.S. Pat. No. 5,418,143 to Zweig and assigned to Avocet Medical Incorporated, Los Gatos Calif., is directed to a method for detecting clot formation in whole blood sample. A test strip is disclosed which comprises a porous membrane having a coagulation initiator and a substate impregnated therein. The substrate is activated by thrombin and produces a detectable fluorescent signal as the output.
Though the above technologies could be considered to be useful in a "point-of-care" environment, these technologies are either complex to build and/or use, or lack reproducibility and/or precision. Often, a very complicated multi-parameter optimization process has to take place to meet basic specifications for point-of-care use. In order to be effective, a device should be simple, be minimally parameter dependent, ease detection and be robust.